Complete response to eculizumab in atypical hemolytic uremic syndrome with homozygous C3 mutation

Case Report: Atypical Hemolytic Uremic Syndrome (atypical HUS) is a rare and severe form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, intravascular hemolysis, and acute kidney injury with an incidence of 1 per million.1 Dysregulation and overactivation of the complement alternative pathway due to genetic mutations have been detected in 40-60% of patients with sporadic or familial atypical HUS.2,4 Triggers include viral illness, pregnancy, malignancy, sepsis, or sporadically with no known inciting event.1 Atypical HUS is a severe disease with a 2-10% risk of mortality, 33% risk of end-stage renal failure, and 50% chance of relapse.5 A 24-year-old female with prior history of atypical HUS at the age of 16 (with response to plasmapheresis) presented to the ER with a 5-day history of fever, chills, sore throat, nausea, vomiting, and dark urine. She tested positive for COVID-19. The exam revealed scleral icterus and scattered petechiae. Labs demonstrated nadir hemoglobin (Hgb) of 9.2 g/dL, platelet count of 52 000k/uL, haptoglobin < 30 mg/dL, peak LDH 1128U/L and creatinine 4.62 mg/dL. Urinalysis is consistent with hemoglobinuria. Schistocytes were noted on the peripheral smear. Rapid streptococcal antigen test and C3, C4, and IgA levels were unremarkable. Chest X-Ray, X-ray KUB, and ultrasound abdomen were unremarkable. The pregnancy test was negative. ADAMTS13 was >100%. Genetic analysis after the initial episode at age 16 revealed autosomal recessive inheritance c.193A > c gene mutations in C3. The patient received IV fluids, ceftriaxone for cystitis, and two units of Fresh Frozen Plasma. She initiated treatment with eculizumab. She also received the MENVEO and meningitis B vaccine per protocol due to the risk of meningitis from terminal complement deficiencies. After 4 infusions of eculizumab, patient's labs improved to platelet count of 307 000 k/uL, Hgb 12.2 g/ dL (nadir 9.2 g/dL), haptoglobin 78 mg/dL normalization of LDH and improved creatinine. Atypical HUS is a rare form of TMAwith mutations in C3 noted in 5% of cases. Complement cascade dysfunction leads to endothelial deposits and microvasculature damage. The resulting prothrombotic state causes obstructive microvascular thrombi predominantly affecting the kidneys but can cause multiorgan dysfunction. The SARS-CoV-2 virus may precipitate atypical HUS relapse due to endothelial damage and complement activation further intensified in patients with existing complement aberrations. Plasma exchange remains a standard of care for atypical HUS, as it effectively removes the antibodies and other proteins. Eculizumab a humanized monoclonal IgG antibody binds to complement proteins, preventing cleavage into C5a and C5b blocking C5b-9(MAC) activation. In patients with CFH, CFI, C3, and CFB mutations, eculizumab is the preferred intervention. Copyright © 2023 Southern Society for Clinical Investigation.

A Series of Catastrophic Events

Case report - Introduction: Catastrophic antiphospholipid syndrome (CAPS) is a rare, life-threatening disease occurring in up to 1% of antiphospholipid syndrome (APS) cases. It was first defined in 1992 and remains a difficult to treat entity with a mortality rate of 37%. We describe a patient with systemic lupus erythematosus (SLE) and CAPS presenting with simultaneous multi-organ injuries who was successfully managed with 'triple' therapy including cyclophosphamide. Case report - Case description: A 42-year-old female presented to her local hospital with chest pain and worsening vision. She had a background of SLE, triple antibody-positive APS (previous DVT, pregnancy loss and strokes), hypertension, a metallic mitral valve, a previous myocardial infarction and pre-existing visual impairment due to a prior intra-cerebral bleed related to anticoagulation. Examination revealed a faint malar rash, cortical blindness and long tract neurological signs. Her ECG showed ischaemic changes and the admission troponin was significantly raised (3773ng/L). An echocardiogram showed new left ventricular dysfunction and a subsequent cardiac MRI was in keeping with coronary artery disease. Investigations showed an acute kidney injury, newly deranged liver function tests and a raised INR (>11, with no bleeding). Complement was normal with a low dsDNA titre. Urinalysis revealed proteinuria and a protein creatinine ratio measured 176mg/mmol. MRI diffusion weighted brain imaging showed acute bilateral occipital and left fronto-parietal infarcts. She had symptoms of a lupus flare with arthralgia and a butterfly facial rash. COVID-19 PCR tests were negative and she had not been recently vaccinated. She was diagnosed with CAPS and transferred to St Thomas' hospital intensive care. On arrival, she received 1mg intravenous vitamin K followed by triple therapy for CAPS: an unfractionated heparin infusion, oral prednisolone 40mg daily, 5 days of plasma exchange and, given her background of SLE, she was treated with intravenous cyclophosphamide (according to the EUROLUPUS regimen). Intravenous methylprednisolone was avoided due to a previous hypertensive encephalopathy reaction. She responded rapidly. Her troponin fell from a peak of 5054 to 294ng/ L, her creatinine settled at a new baseline (232umol/L) and her liver function normalised. She was switched back to warfarin due to her metallic valve and started on aspirin for cardiovascular secondary prevention. She required physical and occupational therapy due to her strokes but recovered well. Case report - Discussion: According to the 2003 criteria, CAPS can be classified as definite when there is evidence of: -3 organs involved, development of manifestations simultaneously or within a week, confirmation by imaging and/or histopathology of small vessel occlusion and positive antiphospholipid antibodies. Probable CAPS is when 3 out of the 4 criteria are present. In this case, three organs were confirmed to be involved with imaging showing cerebral and cardiac ischaemia. Her creatinine rose from a base of 190 to 289umol/L coupled with a high protein creatinine ratio confirming renal involvement. A Budd-Chiari syndrome was also suspected due to deranged liver function tests and INR, though imaging performed after therapy did not confirm this. A biopsy of any of these four organs was not feasible given the severity of her presentation and coagulopathy. There are no randomised controlled trials but data from the CAPS registry guides treatment and management follows a logical approach: anticoagulation to treat thrombosis, glucocorticoids for inflammation and plasma exchange (or IVIG) to remove the circulating autoantibodies. Triple therapy was associated with a reduced mortality compared to no treatment (28.6% versus 75%, respectively). Following analyses from the CAPS registry we also chose to treat with cyclophosphamide, which is associated with improved survival in patients with SLE. This decision was based on the clinical features of an SLE flare as opposed to serological grounds. There have b en reports of rituximab and eculizumab being used successfully in CAPS, though generally as a last resort. As complement activation is seen in animal models of antiphospholipid syndrome thrombosis and rituximab is often used in refractory SLE, they may prove to be promising agents for refractory CAPS. Case report - Key learning points: 1. Prompt recognition and early treatment is vital in managing CAPS 2. Triple therapy with anticoagulation, glucocorticoids and plasma exchange / IVIG is associated with better survival in CAPS 3. Cyclophosphamide is associated with better survival in patients with CAPS and concomitant SLE.

Atypical hemolytic uremic syndrome in a patient with HIV treated with eculizumab: A case report.

Thrombotic microangiopathy defines a group of pathologies characterized by microvascular dysfunction with the concurrence of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. It represents the most frequent microvascular manifestation of human immunodeficiency virus (HIV) infection. We report the case of a man in the seventh decade of life with a recent diagnosis of infection by HIV, who develops hemolytic uremic syndrome, requiring continuous renal replacement therapy and plasma replacement therapy, without response, ADAMTS13 with preserved activity, ruling out other etiologies (infectious, metabolic, and genetic) with successful response to eculizumab.

Quality of Life of Myasthenia Gravis Patients During COVID-19 Pandemic - One Year Follow Up

Purpose: The coronavirus disease 2019 (COVID-19) is the largest pandemic of our times. Pandemics are severe stressors to vulnerable groups (such as patients with chronic diseases) and this highly contagious disease exerts considerable impacts on mental health. We wanted to investigate the possible impact of COVID-19 pandemic on the quality of life (QoL) of myasthenia gravis (MG) patients and potential changes during the period of one year. Methods: Data on the epidemiological and clinical characteristics of MG was collected. We used a selfdesigned questionnaire (consisting of 12 questions), a revised 15-item Myasthenia Gravis Quality of Life Questionnaire (MGQOL15r), a 36-item health survey of the Medical Outcomes Study Short Form (SF36), Hamilton scales for the assessment of anxiety (HAM-A) and depression (HAMD) were used. The actual severity of the clinical manifestation was estimated using MG activities of daily life (MGADL). We reassessed patients in April and May 2021, who were tested during April 2020 using the same questionnaires. Results: The study included 57 adult MG patients. We noticed a statistically significant difference between the results obtained at these two time points regarding scores on MGQOL15r (p<0.05). The obtained scores were significantly better in 2021. Some scores on SF-36 subscales were also better in 2021 than in 2020 (such as social functioning, emotional well-being, role limitation due to emotional problems) (p<0.05). MGQOL15r and SF36 scores correlate with severe clinical manifestation, high scores on HAM-A and HAM-D (p<0.01). Higher scores on HAM-D and fear that MG symptoms will be worse if the patient gets an upper respiratory infection were independent predictors of the lower SF36 scores. Regarding MGQOL15r independent predictors of the higher score were higher scores on HAM-D. Conclusions: QoL of myasthenia gravis patients improved during the pandemic. It is important for healthcare workers to provide professional therapeutic advice and psychosocial support for this population of patients during the pandemic. eP01.04.07 COVID Spike Antibodies in Neuromuscular Conditions: A KU Experience Pasnoor M1, Tajuddin A1, Jawdat O1, Farmakidis C1, Jabari D1, Heim A1, Higgs K1, Dimachkie M1 1The University of Kansas Medical Center, Kansas City, United States Background: Little is known about the immune response to COVID vaccination in immune suppressed neuromusuclar patients. Multiple studies showed variable data regarding the effect of immunosuppression on the immune response to the vaccination. Objective: To evaluate the COVID spike antibody levels in patients with various neuromuscular conditions who received vaccination and assess the effect of immunosuppressive therapies on antibody levels. Method: We performed a retrospective chart review of patients in neuromuscular clinic who had COVID antibody testing. We collected demographic, clinical, diagnostic and treatment information. Descriptive statistics was performed on the data obtained. Results: The total number of patients enrolled in the study were129, 64 male and 65 female . The mean age of the patients enrolled was 64.82 ±14.50 and the mean duration of antibody acquisition since date of last vaccination dose was 172 days. The number of patients on immunosuppressive therapies was 88(68.2%), 47(53.41%) had high antibody titer (>250), 31(35.23%) had low antibody titer (0.4- 250), 9(10.23%) had undetected antibody titer (<0.4) and 1 (1.1%) had detected unmeasured titer. Immunosuppressive therapies included steroids, methotrexate, azathioprine, myophenolate mofetil, eculizumab, efgartigimod, intravenous immunoglobulin and rituximab. The other group of patients who were not on immunosuppressive medication were 41 (31.8%) , 28 (68.29%) showed high antibody titer (>250), 9(21.95%) showed low antibody titer (0.4-250) , 1(2.44%) showed undetected titer (>0.4) and 3(7.32%) had detected unmeasured titer. 50% of patient who were on rituximab showed undetected antibody titer and 60% of patients who received eculizumab had low antibody titer. 4 % of patients on immunosuppressive drugs did not develop adequate spike antibodies levels to vaccination, compared to 24% on no immunosuppressive therapies. Conclusions: Our study reveals modest impact of immunosuppression on COVID spike antibody titer. While this finding is limited by small number of patients and heterogeneity in therapies, age and interval between vaccination and antibody testing, our finding supports the importance of booster vaccine in this patient population.

Immunosuppressive Therapy as Risk Factor for Severe SARS-CoV-2 Infection in Myasthenia Gravis

Importance: Patients with myasthenia gravis (MG) and IST are potentially at increased risk for poor COVID-19 outcome. Objective: To determine whether immunosuppressive therapy (IST) compared to no IST is associated with a higher risk for, first, a symptomatic SARS-CoV-2 infection and, second, a more severe COVID-19 disease course as measured by hospitalization rate and death. Design, setting, and participants: The present study included all available MG patients from the German myasthenia gravis registry, which is a nationwide registry conducted by expert centers since February 2019 (German Clinical Trials Registry DRKS-ID 00024099). Main outcomes and measures: Between May 2020 and June 2021, data were collected on demographics, disease duration, comorbidities, preexistent IST including standard (corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclosporine) and escalation (rituximab, eculizumab) IST, thymectomy, COVID-19 characteristics, and outcomes. COVID-19 was diagnosed with a nasopharyngeal swab by polymerase-chain-reaction. Multiple binary logistic regression models and generalized estimation equation regression models based on matched SARS-CoV-2 infected to non-infected patients were used to estimate the association of IST with SARS-CoV-2 infection. Multiple binary logistic regression models were used to assess the association of IST with outcome of COVID-19 in MG patients. Results: Of 1388 MG patients, 95 (7%) MG patients with a mean age of 58 (SD 18) and median disease duration of 65 months (IQR 27-126) presented with COVID-19. Among them, 39 patients (41%) were male, and 76 (80%) received IST at the time of infection. There were 32 patients (34%) admitted to hospital due to COVID-19, 12 (13%) to the intensive care unit, and a total of 11 patients (12%) died. IST was a risk factor for hospitalization and death in the group of COVID-19 affected MG patients (adjusted odds ratio [OR] 3.04, 95% confi- dence interval [CI] = 1.02-9.06, p=0.046), but not for symptomatic SARS-CoV-2 infection itself in the whole group of MG patients. Conclusions and relevance: In MG patients, preexistent IST was a factor for a severe disease course of COVID-19 but not for the risk for SARS-CoV-2 infection. These data support the consequent implementation of effective strategies to prevent COVID- 19 in this high-risk group.

Effectiveness of Eculizumab Treatment for Generalized Myasthenia Gravis in Us Clinical Practice: GMG Registry Data

INTRODUCTION: Clinical trial data have demonstrated that eculizumab improves clinical outcomes in individuals with refractory generalized myasthenia gravis (gMG). Data from clinical practice on treatment patterns and effectiveness of eculizumab in gMG are being collected by the Alexion-sponsored gMG Registry. OBJECTIVE: To describe treatment outcomes and safety (serious adverse events [SAEs]) in current gMG Registry participants during eculizumab therapy in clinical practice in the USA. METHODS: Starting in December 2019, adults with gMG who had ever received eculizumab enrolled in the gMG Registry (NCT04202341). After obtaining consent, demographic data, myasthenia gravis activities of daily living (MG-ADL) total score and Myasthenia Gravis Foundation of America (MGFA) classification were collected from medical records at two time points: In the 6 months before eculizumab initiation and at first gMG Registry assessment after eculizumab treatment initiation (at Registry enrollment). SAEs in patients receiving eculizumab during Registry participation were recorded. RESULTS: As of November 29, 2021, in total, 111 adults with gMG had enrolled in the gMG Registry (male, 52.3%;mean [range] age at MG diagnosis, 56.1 [16.0-92.0] years). The mean (range) time from eculizumab initiation to gMG Registry enrollment was 2.0 (0.0-6.7) years. Mean (standard deviation) MG-ADL total score decreased from 8.3 (3.6) before eculizumab initiation to 3.1 (3.6) after eculizumab treatment. MGFA classification improved with eculizumab treatment: Class I, 0.0% of patients before eculizumab initiation versus 28.9% after eculizumab treatment;class II, 36.8% versus 55.3%;class III, 52.6% versus 15.8%;class IV, 10.5% versus 0.0%. The median MGFA class was III before eculizumab initiation and II after eculizumab treatment. One SAE (invasive pulmonary aspergillosis) considered by the investigator to be related to eculizumab was reported in a patient who died, and two serious infections considered unrelated to eculizumab were reported (COVID-19/pneumonia and urinary tract infection);there were no meningococcal infections. Two patients died of causes considered to be unrelated to eculizumab (lung adenocarcinoma and acute congestive heart failure/myocardial infarction). CONCLUSION: These data from the gMG Registry provide evidence of the effectiveness of eculizumab for the treatment of gMG in clinical practice across the USA, demonstrating a benefit/risk profile consistent with that observed in clinical trials.

Myasthenic Crisis

Myasthenia gravis (MG) is an acquired autoimmune disorder of the neuromuscular junction, caused by antibodies that target the post-synaptic membrane. These antibodies most commonly bind to the nicotinic acetylcholine receptor (AChR), but in a smaller proportion of cases, antibodies to muscle specific tyrosine kinase (MuSK)(1-10%) or to lipoprotein receptor-related protein 4 (Lrp-4)(1-3%) can be present instead. These antibodies act on the receptors, prevent neuromuscular transmission and induce weakness of skeletal muscles. In 10-15% of MG patients, no antibodies are detected and these patients are designated as seronegative. Weakness can be generalized or localized, is usually more proximal than distal, and nearly always includes eye muscles, causing diplopia and/or ptosis. The pattern of involvement is usually symmetric, except for the eye involvement, which is mostly markedly asymmetric. The muscle weakness typically increases with exercise and repetitive muscle use (fatigue) and varies over the course of a day and from day to day. Patients commonly present first with ocular manifestations, however, the majority develop generalized muscle weakness, involving the facial and bulbar muscles (dysarthria, dysphagia), the limbs, the neck and axial muscles (dropped head, bent spine), and in severe cases the diaphragmatic and intercostal muscles. MuSK-MG predominantly appears in women, who show weakness in mostly cranial and bulbar muscles, commonly with an acute onset and a tendency to rapid progression in comparison to AchRMG. Myasthenic crisis (MC), the severe end of the disease spectrum, can occur at any age and is potentially life-threatening. This is a clinical emergency that requires management in an intensive care setting. MC is mostly provoked by infections or inadequate treatment. In 15-40% of the reported patients with COVID-19 infection a MC occurred. MC appears in around 15-20% of MG patients in the first 2 years after diagnosis. MC can be the first manifestation of MG. Up to a half of MuSK-MG patients develop a MC in their disease course and it is also common in patients with thymoma-associated disease, or AChR-positive late-onset disease;after surgery (including thymectomy);during or after childbirth;in patients taking a contraindicated medication;at the start of corticosteroid treatment or during the tapering of immunosuppression. In approximately 20% the cause of an exacerbation remains unknown. Characteristic symptoms for the impending MC include rapidly progressive muscle weakness, 'inverse aspiration', dysphagia with choking, and dyspnoea associated with orthopnoea and/or tachypnoea which can result in respiratory insufficiency. The clinical management of MC with mechanical ventilation, extended intensive care management and intravenous immunoglobulins (IVIg) or plasmapheresis (PLEX) or in case of persistent MC escalation with rituximab has led to a significant decline in mortality from around 40% in the early 1960s to 5-22% in recent studies with negative prognostic factors including older age at onset, prolonged intubation, and associated comorbidities. At present IVIg and PLEX are considered the gold standard treating MC. However, it may be conceiv- able that newly developed monoclonal antibody therapy (eculizumab, efgartigimod), could be used as rescue therapy to achieve a significant and rapid clinical improvement.

Atypical Hemolytic Uremic Syndrome after SARS-CoV-2 Infection: Report of Two Cases.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease causing systemic thrombotic microangiopathy (TMA) due to the fact of complement dysregulation. Immune activation by viruses, including SARS-CoV-2, can lead to the development of an episode of aHUS against a background of genetic dysregulation in the complement pathway. This paper presents an analysis of two cases of aHUS-siblings diagnosed with familial disease, with a genetic predisposition to aHUS, in whom infection with SARS-CoV-2 was a strong trigger of disease recurrence. The quick recognition and treatment with eculizumab in the early stage of the disease resulted in a rapid improvement in clinical conditions and laboratory parameters.

Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

EFFICACY, TREATMENT ADMINISTRATION SATISFACTION AND SAFETY OF SUBCUTANEOUS RAVULIZUMAB THROUGH 1 YEAR IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO RECEIVED PRIOR INTRAVENOUS ECULIZUMAB

Background: The efficacy of ravulizumab (intravenous [IV] formulation;administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day-1 to day-30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab;all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline;incidence of breakthrough hemolysis;transfusion avoidance;and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84;IV/SC: n = 44;mean [range] duration of SC treatment: 486.4 [37-709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%);no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%);injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image: Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

POS-011 PRIMARY ATYPICAL HEMOLYTIC-UREMIC SYNDROME ASSOCIATED WITH COVID-19: A BRIEF REVIEW

Introduction: Since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in December 2019, coronavirus disease 2019 (COVID-19) has spread tremendously. We now know that infected individuals can experience a wide range of systemic complications, including thrombotic microangiopathy (TMA). Among the total of 45 published cases of COVID-19-associated TMA, there were 4 cases of primary atypical hemolytic-uremic syndrome (aHUS). COVID-19 likely represents a second hit of primary aHUS that manifests in genetically predisposed individuals. Methods: We reviewed the global literature reported from the first mention of COVID-19 in 2019 to February 2022, including individual case reports and case series of adult patients with COVID-19-associated TMAs. Electronic searches were conducted in the PubMed database using keywords and their combinations: »thrombotic microangiopathy, COVID-19, thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome«. Results: Among the total of 45 published cases of COVID-19-associated TMA, there were 18 cases reported as acquired thrombotic thrombocytopenic purpura (TTP) and 19 cases presented as mixed forms of TMA associated with multifactorial triggers (without proven abnormalities of ADAMTS13 activity or proven inhibitors of ADAMTS13 or proven Shiga toxin). The remaining 8 cases were complement-mediated TMAs: • 2 cases of hereditary aHUS (patient 1 and 2);• 1 case of probable hereditary aHUS, where the patient had a heterozygous variant with unknown significance in complement factor I and was heterozygous for the complement factor H H3 haplotype reported as a risk factor of aHUS (patient 3);• 1 case of aHUS with significantly elevated factor H autoantibodies in the absence of genetic testing (patient 4);• 4 cases with decreased complement levels in the absence of genetic testing. We focused on the 4 patients with primary aHUS. Among those, there were 2 females and 2 males with an average age of 28.75 +/- 6.18 years. Although in all cases nasopharyngeal swab was positive for SARS-CoV-2 infection by a polymerase chain reaction-based test, none of the patients had any respiratory symptoms. Patients 2 and 3 underwent renal biopsies, which confirmed the diagnosis of TMA. Patients 2, 3, and 4 required treatment with hemodialysis (HD). Patient 3 did not receive any specific treatment due to delayed diagnosis and lack of availability of eculizumab, while patients 2 and 4 underwent therapeutic plasma exchange and received steroids and eculizumab (patient 2 received only the initial dose of eculizumab because further doses were not granted). Patients 2 and 3 remained HD-dependent, while the renal function of patient 4 partially recovered. Patient 1, who did not need HD, was treated with eculizumab and had partial recovery of renal function. Conclusions: In conclusion, different types of TMA may occur during the course of COVID-19, including aHUS. COVID-19 likely represents a second hit of primary aHUS that manifests in genetically predisposed individuals (e.g., those with an underlying complement risk factor). Early identification of COVID-19-associated primary aHUS is needed in order to promptly start treatment with eculizumab. No conflict of interest

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

Various effective monoclonal antibodies (mAbs) have been approved for both multiple sclerosis (MS) and anti-aquaporin-4-seropositive neuromyelitis optica spectrum disorders worldwide, including in Japan. As these newer mAbs have distinct modes of action that effectively suppress the recurrence of inflammation and slow disability progression, they can modulate and interfere with the protective immune response against pathogens, resulting in various infectious complications. Among various mAbs, natalizumab (NTZ) has the highest risk of causing progressive multifocal leukoencephalopathy (PML), a rare but fatal opportunistic brain infection caused by John Cunningham polyomavirus. Switching from NTZ to B-cell-depleting mAbs, such as ocrelizumab, is also a possible risk factor for PML development. Alemtuzumab carries the risk of reactivation of varicella-zoster virus (VZV);therefore, prophylactic acyclovir treatment is required. NTZ has also been associated with VZV reactivation. Eculizumab can cause severe meningococcal infection due to Neisseria meningitis, and vaccination prior to treatment induction is required. Attention to the reactivation of hepatitis B or Mycobacterium tuberculosis is also needed during mAb therapy. Additionally, in the era of severe acute respiratory syndrome coronavirus 2 infection (COVID-19), the risk for of developing severe COVID-19 may be associated with some mAbs, such as B-cell-depleting agents. Thorough understanding and mitigation strategies for infectious risks are essential.

Real-world experience of eculizumab treatment for generalized myasthenia gravis: initial data from a registry of patients with generalized myasthenia gravis in the USA

Objective: To describe the baseline characteristics and interim treatment outcomes of registry participants with generalized myasthenia gravis (gMG) treated with eculizumab in real-world clinical practice in the USA. Background: Clinical trials have shown that eculizumab improves clinical outcomes in individuals with refractory gMG. The Alexion-sponsored gMG Registry collects real-world data on treatment patterns and effectiveness of eculizumab in gMG. Design/Methods: Adults with gMG who had ever received eculizumab enrolled in the Alexion-sponsored gMG Registry (NCT04202341) from December 2019. After consent, demographic data, Myasthenia Gravis (MG) activities of daily living (ADL) total scores, MG Foundation of America (MGFA) classification and serious adverse events (SAEs) were collected from medical records at two time points: before eculizumab initiation (within prior 6 months) and at Registry enrollment (first Registry assessment during eculizumab treatment). Results: As of February 28, 2021, 59 adults with gMG had enrolled in the Registry (male, 54.2%;mean [range] age at MG diagnosis, 58.3 [16.0-84.0] years). Mean (range) time from eculizumab initiation to Registry enrollment was 697.1 (7.0-2435.0) days. Mean (standard deviation) MG-ADL total score decreased with eculizumab, from 8.3 (3.71) before eculizumab to 3.1 (3.43) at first Registry assessment during treatment (n=38). MGFA classification improved with eculizumab (n=32): before eculizumab, MG was class I (0.0% of patients), II (40.6%), III (53.1%) or IV (6.3%);at first Registry assessment during treatment, MG was class I (25.0%), II (62.5%), III (12.5%) or IV (0.0%). SAEs (lung adenocarcinoma, respiratory failure, atrial fibrillation, heart failure, colostomy closure, COVID-19, death) were reported in six patients. There were two deaths (unrelated to eculizumab). No meningococcal infections were reported. Conclusions: Initial analyses of Registry data showed that MG-ADL total score and MGFA classification improved with eculizumab, and that eculizumab was generally well tolerated. These findings provide additional evidence of the effectiveness of eculizumab for treating gMG in real-world clinical practice.

A RARE CASE OF SECONDARY HAEMOLYTIC UREMIC SYNDROME AFTER ANTI-SARS-COV-2 VACCINATION

BACKGROUND AND AIMS: Haemolytic uremic syndrome (HUS) is a rare disease characterized by macroangiopathic haemolytic anaemia, thrombocytopaenia and severe AKI, belonging to the thrombotic microangiopathies (TMAs). It is divided into typical and atypical HUS: the first one occurs most frequently in children within the first 5 years of life and it is associated with Shiga-like toxin producing Escherichia coli infection;the second one (aHUS) is less common (10%) and it is due to complement abnormalities with coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs or pregnancy. There is an increasing interest in SARS-CoV-2 infection as new trigger for complement activation. Nine cases of aHUS were recently associated with COVID-19, most of them occurring within 1 month from the infection. Available data suggest that SARS-CoV-2 is a potential trigger for aHUS: it can induce an over inflammatory state and to activate coagulation and complement pathway. Likewise, mRNA-based vaccines against COVID-19 inducing the expression of SARS-CoV-2 spike protein to stimulate immune recognition and antibody response could be a suitable trigger for HUS. METHOD: We report the case of a 17-year-old woman, who presented at our emergency department with fever, dyspnoea, acute kidney injury AKI III with anuria, hypertension, severe anaemia, no diarrhoea, severe thrombocytopaenia and myocarditis, about 2 weeks after the first administration of SARS-CoV-2 vaccine (Comirnaty) and recent exposition to SARS-CoV-2 positive individual. SARS-CoV-2 nasal PCR swab was negative (as well as successive ones) and she was immediately admitted to paediatric intensive care unit and treated with transfusions and haemodialysis. Laboratory exams suggested a thrombotic microangiopathy with normal ADAMTS-13 activity and no E. coli infection. She underwent a renal biopsy that confirmed our hypothesis of aHUS: wrinkled capillaries, subendothelial expansion, mesangiolysis and rare thrombi in capillaries lumen. Arterioles had intimal proliferation with mucoid oedema who gave rise to onionskin like lesion that obliterates lumens. One glomerulus showed extracapillary proliferation (crescent), and there was interstitial lymphomonocytic inflammatory infiltration in the nearby. Also signs of acute tubular injury and atrophy were reported. Positive stain to fibrinogen in the arterioles at immunohistology was noted. She immediately performed genetic exams for aHUS-related complement mutations and she started immunosuppression with corticosteroids and eculizumab infusions. After 2 months of eculizumab, she was still oliguric, requiring renal replacement therapy. Genetic analysis showed no mutations. Therefore, she was examined for other genetic causes of thrombotic microangiopathies. RESULTS: Finally, came to light that she had high levels of homocysteine, and she was diagnosed with secondary HUS associated with cobalamin C deficiency, which manifests with methylmalonic aciduria and homocystinuria due to a recessive mutation in the MMACHC gene, causing a cobalamin C type deficiency, which is the common functional variant of vitamin B12. After metabolic therapy with hydroxocobalamin, she gradually recovered diuresis and partially renal function without need for replacement therapy. CONCLUSION: Reports from immunization programs show as myocarditis and thrombotic thrombocytopaenia are considered among main serious complications caused by COVID-19 vaccines, representing 12.6 cases per million doses and 0.73 cases per 100 000, respectively. This interesting case probably supports data about the role of mRNA-based anti- SARS-CoV-2 vaccines like a precipitant factor for TMAs. Moreover, our patient turned out to be an extremely rare case of HUS secondary to cobalamin C deficiency, that is generally diagnosed in early infancy and show typically neurological symptoms (absent in our case). Probably, the mRNA-based vaccine acted like 'a second hit', but existing predisposition should always be investigated including also the les frequent forms. (Table Presented).

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Management of atypical Hemolytic-Uremic Syndrome in gravida with SARS-COVID-2 infection

Background. Coronavirus disease is a highly contagious infection that can be deadly and is caused by the severe acute respiratory syndrome SARS-CoV-2.The current literature indicates that pregnancy may worsen the course of COVID-19 infection compared to non pregnant women at the same age. Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated disorder, characterized by microangiopathic hemolysis, thrombocytopenia, and renal failure. Case presentation. A case of a gravida at 20 weeks of gestation with worsening clinical conditions due to aHUS, and SARS-COV-2 infection was managed. Continuous renal replacement therapies with transfusion of plasma was started. Diagnosis comprised atypical HELLP presentation with progressive reduction of PLT levels versus other thrombotic microangiopathy. Conclusions. The lack of anti-ADAMTS 13 antibodies allowed to make the diagnosis of Hemolytic-Uremic Syndrome (HUS). The patient started therapy with Eculizumab 900 mg that was administered one time every 7 days. The patient resumed spontaneous urination after one day of therapy. Renal failure persisted after 5 days with creatinine levels at 7.9 mg/dL and azotemia at 126 mg/dL. It is challenging to predict the impact of immune-mediated therapies on pregnant women. Furthermore, additional data about the immunomodulatory changes in COVID-19 patients during pregnancy may reveal pathophysiological events behind this deadly disease.

TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY SUCCESSFULLY TREATED WITH RAVULIZUMAB

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell therapy (HSCT) with incidence rates ranging from 10-35%. The predominant mechanism leading to TA-TMA is endothelial cell damage leading to complement dysregulation and microvascular hemolysis. Complement dysregulation is particularly important in the pathophysiology of TA-TMA as initial trials have shown response to complement blockade using eculizumab, a humanized monoclonal antibody targeting the terminal complement pathway. Ravulizumab is a longer acting monoclonal antibody with the same target as eculizumab that is increasingly used for treatment of atypical hemolytic uremic syndrome. Herein, we describe the case of an African American female with relapsed/refractory infantile B-cell acute lymphoblastic leukemia (B-ALL) who underwent 10/10 HLA-matched sibling donor allogeneic transplant (conditioning: busulfan/fludarabine/thiotepa;GVHD prophylaxis: tacrolimus/methotrexate) who developed TA-TMA marked by pericardial effusion, elevated LDH, proteinuria, hypertension, thrombocytopenia, anemia, and evidence of microangiopathy. Upon diagnosis, as ravulizumab was on formulary and readily available unlike eculizumab, she was treated with ravulizumab instead of eculizumab. Objectives: To describe the therapeutic response to ravulizumab in one patient diagnosed with TA-TMA. Design/Method: A retrospective chart review was performed regarding this patient's ravulizumab treatment course, and direct discussions were had with the patient's care team. Results: Ravulizumab (loading dose of 600 mg followed 2 weeks later by maintenance dosing of 600 mg every 4 weeks) was administered. Pre-treatment CH50 was >75 U/mL (range: 30-75 U/mL) with sC5b9 and C3 complement levels at the upper limit of normal at 220 ng/mL (range: ≤244 ng/mL) and 143 mg/dL (range: 72-164 mg/dL), respectively. Clinical normalization of the patient's TA-TMA was achieved two weeks after loading dose administration with normalization of LDH and blood pressure values, improved proteinuria, decreased transfusion requirements, absence of schistocytes on peripheral smear, and complete resolution of pericardial effusion. A total of 5 maintenance doses of ravulizumab were administered approximately every 4 weeks with CH50 ranging <3-33 U/mL during this time period. Five maintenance doses were administered as the optimal duration was unknown and the patient's TA-TMA treatment course was complicated by COVID-19 infection, for which there was concern could lead to TA-TMA reactivation (which did not occur). The ravulizumab was well tolerated throughout with amoxicillin used for meningococcal prophylaxis. Conclusion: While studies evaluating ravulizumab for treatment of TA-TMA are ongoing, ravulizumab successfully led to complement blockade and clinical improvement in this patient with TA-TMA.

Comparison of Chest Computed Tomography Differential Diagnosis of Ground Glass Opacities in the COVID-19 Patients

Aim: To compare chest computed tomography (CT) diagnosis of ground glass opacities in the COVID-19 patients. Study design: Retrospective study. Place and duration of study: Department of Radiology, Ghulam Muhammad Mahar Medical College Sukkur from 1st July 2020 to 31 August 2021. Methodology: Fifty patients on differential CT diagnosis of ground glass opacities seen in COVID 19 patients were enrolled. Thoracic CT images by applying auto exposure-control settings and ranges of scan were done. The noise-index was kept as 12.3. Using helical 16 slice Alexion CT-Toshiba. Keeping a comparison with viral infection CT images a list of 7 signs which were positive for Covid CT scan were recorded. Peripheral lesions meant any lesions which effects peripheral area up to 3 to 4 cm lung periphery with/without having central dispersal. A hazy-opacity was termed as ground glass. Results: Mean age of the patients was 49.1±10.2 years with 27 (54%) males and 23(46%) females. Mix ground glass opacitites and consolidation were also the features of the CT imaging in coronavirus posisitve cases. Man-Whitney test results showed that combined-CT scoring had a SE value as 0.044 with a confidence interval between 0.756-0.927. Comparing the differential CT values within COVID and non COVID patients based on RT PCR results it was observed that posterior region lower lobe involvement was a feature of COVID-19 patients while crazy paving pattern and peripheral distribution was also seen in corona patients. Conclusion: Present study highlights that chest CT helps in differentitaing corona virus from other causes of pneumonias and grond glass opacities.

A Review on Current Side Effects of Used Drugs During Treatment of Patients With COVID-19

Background: Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To increase the success in treating patients with COVID-19, many drug suggestions and some clinical studies are shared in the literature. However, the combination of several drugs with other clinical care has improved patients’ conditions. And this review discusses some side effects of Covid-19 drugs’ adverse effects. Objectives: Here, we have shortly reported the recent updates on the most common and plausible drugs for treating COVID-19 patients. We also compare these treatment options based on their impact on symptom management, inpatient length of stay, and overall morbidity and mortality. Methods: An extensive literature search was performed through PubMed, Scopus, Web of Science, and Google Scholar. Most of the keywords used were: "COVID-19", "Side effects of used drugs," "Treatment of COVID-19", "Risk factors," "Organ damage," and "Methods of diagnosis and treatment." Results: Anti-inflammatory, antimicrobial, and vitamin supplements do not have obvious benefits, but there is limited information to consider. Other factors and drugs such as improved plasma, eculizumab, immunoglobulins, IgG1-neutralizing monoclonal antibodies, remidseiver, steroids, and tosilizumab have shown potential effects on patient’s length of hospital stay and mortality. Currently, there is no evidence that any other vaccines, apart from those specifically designed for the SARS-Cov-2 virus, will protect against COVID-19. Conclusion: Since the prevention of the COVID-19 virus is a new issue in the medical world, there is no known effective treatment option in this area, and the prevention of its adverse side effects has not been conclusively proven. Of course, the occurrence of side effects in patients undergoing treatment such as hepatotoxicity, retinal damage, nephrotoxicity, and cardiotoxicity proves that the necessary caution should be used in drug combination methods.